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CB2 cannabinoid receptor targets mitogenic Gi protein–cyclin D1 axis in osteoblasts
Author(s) -
Ofek Orr,
AttarNamdar Malka,
Kram Vardit,
DvirGinzberg Mona,
Mechoulam Raphael,
Zimmer Andreas,
Frenkel Baruch,
Shohami Esther,
Bab Itai
Publication year - 2011
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.228
Subject(s) - cyclin d1 , mapkapk2 , creb , chemistry , medicine , endocrinology , osteoblast , protein kinase a , phosphorylation , cyclin d , cannabinoid receptor type 2 , pertussis toxin , signal transduction , microbiology and biotechnology , cancer research , receptor , cyclin dependent kinase 2 , biology , cell cycle , g protein , cannabinoid receptor , agonist , biochemistry , cell , transcription factor , in vitro , gene
CB2 is a Gi protein–coupled receptor activated by endo‐ and phytocannabinoids, thus inhibiting stimulated adenylyl cyclase activity. CB2 is expressed in bone cells and Cb2 null mice show a marked age‐related bone loss. CB2‐specific agonists both attenuate and rescue ovariectomy‐induced bone loss. Activation of CB2 stimulates osteoblast proliferation and bone marrow derived colony‐forming units osteoblastic. Here we show that selective and nonselective CB2 agonists are mitogenic in MC3T3 E1 and newborn mouse calvarial osteoblastic cultures. The CB2 mitogenic signaling depends critically on the stimulation of Erk1/2 phosphorylation and de novo synthesis of MAP kinase–activated protein kinase 2 ( Mapkapk2 ) mRNA and protein. Further downstream, CB2 activation enhances CREB transcriptional activity and cyclin D1 mRNA expression. The CB2‐induced stimulation of CREB and cyclin D1 is inhibitable by pertussis toxin, the MEK‐Erk1/2 inhibitors PD098059 and U0126, and Mapkapk2 siRNA. These data demonstrate that in osteoblasts CB2 targets a Gi protein–cyclin D1 mitogenic axis. Erk1/2 phosphorylation and Mapkapk2 protein synthesis are critical intermediates in this axis. © 2011 American Society for Bone and Mineral Research.